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In locally advanced squamous cell carcinoma of base of tongue tumors concomitant chemoradiotherapy with infusional cisplatinum and 5 fluorouracil results in higher disease free and overall survival as compared to radiotherapy as single modality. This better tumor response with chemoradiotherapy comes at cost of higher incidence of mucosal toxicity.

Background: BMN 673 is the most potent and specific inhibitor of poly-ADP ribose polymerase (PARP) 1 and 2 in clinical development (IC50<1nM). In BRCA-related tumors, which are genetically dependent on PARP-mediated DNA repair by base excision repair, PARP inhibition induces synthetic lethality. Initial phase 1 results have been presented (de Bono et al JCO 31:5s, 2013 suppl; abstr 2580), showing good tolerability and anti-tumor activity with an MTD on a daily, oral dosing schedule of 1000 μ/day. Methods: In this 2-stage study, patients with solid tumors including BRCA-related cancers, were enrolled during dose-escalation followed by an expansion phase at the MTD in breast, ovarian, and pancreatic cancer patients with deleterious germline BRCA mutations and in small cell lung cancer and Ewing sarcoma patients to further characterize safety and efficacy. This abstract summarizes demographics and safety for all patients and efficacy for patients with BRCA-related cancers. Results: As of 17May2013, a total of 1 pancreatic, 18 breast (17F/1M), and 28 ovarian cancer pts with germline BRCA mutations were enrolled at doses from 100-1100 μg/day. All breast cancer patients were treated from 900-1100 μg/day. The median (range) age for all 70 patients is 51.5 (18-81), PS 0 (0-1) and # of prior therapies 4 (1-13), with 47 patients having deleterious BRCA mutations. An MTD of 1000 μg/day was established with thrombocytopenia being dose-limiting. Related adverse events occurring in > 10% of all 70 patients included fatigue, nausea, alopecia, anemia, thrombocytopenia and neutropenia. One patient has had related grade 4 thrombocytopenia. Grade 3 related AE's included fatigue in 1 patient (1%), anemia and thrombocytopenia in 9 each (13%) and neutropenia in 4 (6%). Dose reductions occurred in 11 pts due to myelosuppression. No patients discontinued for adverse events. Response in Germline BRCA PatientsBRCA Tumor TypeNDose Range (μ/day)ResponseBreast18900-11001CR/6PR/5SD≥12 weeksOvarian28100-11001CR/10PR/19GCIG/4SD≥24 weeksPancreas110001 SD ≥ 12weeksTwo of 2 BRCA breast responders had responded to prior platinum while 0 of 4 non-responders to prior platinum responded to BMN 673. Five of 12 breast cancer pts with no prior platinum have responded. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with deleterious germ line BRCA mutations. Myelosuppression and fatigue are the primary side effects associated with need for dose reduction. A phase 3 trial in metastatic breast cancer patients with deleterious germ line BRCA mutations is planned with single-agent, once-daily oral dosing of 1000 μg (1 mg) per day. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-02.

Background: Nal-IRI (MM-398, nanoliposomal irinotecan) is designed for extended circulation relative to free irinotecan and to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Tumor deposition of nal-IRI and subsequent conversion to SN-38 in both neoplastic cells and tumor associated macrophages (TAM) may positively correlate with response to therapy. In phase I studies of nal-IRI, activity has been shown in metastatic breast cancer (MBC), pancreatic and colorectal cancer. Ferumoxytol (FMX) is an iron-oxide superparamagnetic nanoparticle that has been used off-label for its MRI contrast properties. FMX has long-circulating pharmacokinetics and is taken up by TAMs with similar distribution patterns to nal-IRI in preclinical models. A single site pilot study established the feasibility of performing quantitative FMX MRI. Thirteen patients with advanced cancer (3 with ER/PR+ MBC) were imaged with FMX MRI and treated with nal-IRI. Median tumor lesion FMX uptake in the pilot study was 32.6 and 34.5 μg/mL at 1 h and 24 h, respectively. Lesions with FMX uptake above the median were associated with greater reductions in tumor size following treatment with nal-IRI as determined by CT lesion measurements. The relationship between FMX levels in tumor lesions and nal-IRI activity may serve as a potential biomarker for nal-IRI deposition and response in solid tumors. This study has been expanded to include additional MBC patients to further evaluate the technical feasibility of FMX MRI at multiple study sites, and to evaluate activity of nal-IRI in patients with MBC. Trial Design: Three cohorts of 10 patients with MBC in the following categories will be enrolled: ER and/or PR positive/HER2-negative, triple negative (TNBC) and MBC with brain metastases. An imaging phase will be followed by a treatment phase. The imaging phase consists of a baseline MRI scan, FMX infusion, and follow-up MRI scans at 1-4 and 24 h after infusion. The treatment phase begins 1-6 days after imaging and consists of nal-IRI 80 mg/m2 q2w. A pretreatment biopsy is required for correlative studies. Study Objectives: The primary objective of this multisite expansion is to investigate the feasibility of FMX quantitation in tumor lesions at multiple lesion sites in breast cancer. The secondary objective is to characterize the efficacy of nal-IRI in patients with metastatic breast cancer. Eligibility Criteria: The key inclusion criteria include patients with MBC, ECOG 0 or 1 with adequate bone marrow reserve and no prior topoisomerase 1 inhibitor or anti-VEGF treatment. ER and/or PR positive/HER2-negative and TNBC patients must have had 1-3 prior lines of chemotherapy in the metastatic setting and have at least 2 measurable lesions. Patients with brain metastasis must be neurologically stable and have new or progressive brain metastases after prior radiation therapy with at least one lesion measuring ≥ 1 cm in longest diameter on gadolinium-enhanced MRI. Status: This trial is currently recruiting patients. Citation Format: Sachdev JC, Ramanathan RK, Raghunand N, Anders C, Munster P, Minton S, Northfelt D, Blanchette S, Campbell K, Lee H, Klinz SG, Hendriks BS, Moyo V, Fitzgerald JB, Korn RL. A phase 1 study in patients with metastatic breast cancer to evaluate the feasibility of magnetic resonance imaging with ferrumoxytol as a potential biomarker for response to treatment with nanoliposomal irinotecan (nal-IRI, MM-398). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-14.

Background: Most patients diagnosed with breast cancer have ER+ tumors. Treatment of ER+ MBC typically involves endocrine therapy, including aromatase inhibitors and selective ER modulators such as tamoxifen; however, many patients develop resistance. Fulvestrant, an ER antagonist, is a commonly prescribed second- or third-line therapy for postmenopausal patients who have progressed on endocrine therapy; although, most patients will eventually develop resistance to this drug as well. It was hypothesized that CC-486, an oral formulation of azacitidine, may resensitize patients to endocrine therapy and possibly delay resistance to fulvestrant through the epigenetic regulation of certain genes. Methods: 97 postmenopausal female patients aged ≥ 18 years with ER+, HER2− MBC refractory to an aromatase inhibitor were randomized 1:1 to receive CC-486 300 mg on days 1 through 21 and fulvestrant 500 mg on days 1 and 15 of cycle 1 and day 1 of subsequent 28-day cycles or the same fulvestrant regimen alone. The primary endpoint was progression-free survival (PFS) based on investigator's assessment using RECIST version 1.1 and summarized by the Kaplan-Meier method. A Cox proportional hazards model was used to estimate the hazard ratio (HR; including a 2-sided 95% CI), and a log-rank test was used to calculate P values for comparisons between treatment arms. Key secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. Results: 48 patients were included in the CC-486 + fulvestrant arm and 49 in the fulvestrant-alone arm. Median age was 63 years. Baseline characteristics were generally balanced between treatment groups, with some exceptions. The CC-486 + fulvestrant treatment cohort had fewer patients aged ≥ 65 years (40% vs 49%), with an ECOG PS of 1 (25% vs 57%), or with liver metastases (29% vs 43%) than did the fulvestrant-alone cohort. At the time of this analysis, 36 patients (75%) in the CC-486 + fulvestrant arm and 40 patients (82%) in the fulvestrant-alone arm had discontinued treatment, mostly due to progressive disease (81% and 90%, respectively). Median PFS was 5.5 months in both treatment groups (HR 0.87; 95% CI, 0.54 - 1.42; P = 0.599). ORR was 8.3% vs 2.0% in patients receiving CC-486 + fulvestrant vs fulvestrant alone, respectively. Median OS has not been reached. In patients who received CC-486 + fulvestrant, the most common any-grade nonhematologic treatment-emergent adverse events (TEAEs) were nausea (78%), vomiting (78%), diarrhea (44%), and constipation (41%), and the most frequent any-grade hematologic TEAE was neutropenia (26%). Of patients who discontinued due to AEs, most patients receiving CC-486 + fulvestrant treatment discontinued due to gastrointestinal (GI) TEAEs. Conclusion: The addition of CC-486 to fulvestrant did not improve PFS in patients with ER+, HER2− MBC compared with fulvestrant alone, and GI TEAEs were reported in a majority of patients. These results do not support further evaluation of this combination in this setting. Citation Format: Campone M, Sachdev J, Bianchi GV, Beck JT, Martínez-Jáñez N, Cortes J, Schmidt M, Zamagni C, Chen P, Miller J, Fandi A, Gianni L. Efficacy and safety results from a randomized, phase II study of CC-486 in combination with fulvestrant in postmenopausal women with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-07.